tbuckley/cabot-search huggingface dataset:
Hypermetabolic Esophagitis Dessicans Superficialis Mimicking Esophageal Cancer on FDG PET/CT
Authors: Tatiana Mamaliga, Yiyan Liu
Journal: Clinical Nuclear Medicine (2022)

Abstract An 83-year-old man with history of multiple myeloma obtained an FDG PET/CT for surveillance. Although there was no evidence of metabolically active myeloma, an incidental highly FDG-avid focus was noted at the gastroesophageal junction. Findings were interpreted as malignancy. The patient underwent esophagogastroduodenoscopy, which showed nonerythematous desquamation of the distal esophagus consistent with esophagitis dessicans superficialis (EDS) without any evidence of malignancy. There is paucity of literature regarding EDS and its image findings. This case illustrates an instance of focal mass-like uptake on FDG PET/CT, which represents an endoscopy- and pathology-confirmed EDS and mimics esophageal cancer.
HGG-12. Rapid PTEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy
Authors: Faye Walker, Lays Martin Sobral, Etienne Danis, Bridget Sanford, Ilango Balakrishnan, Dong Wang, Angela Pierce, Sana Karam, Natalie Serkova, Nicholas Foreman, Sujatha Venkataraman, Robin Dowell, Rajeev Vibhakar, Nathan Dahl
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-mediated promoter proximal pause-release of Pol II is a conserved regulatory mechanism for synchronous transcriptional induction best described in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. DESIGN/METHOD: In order to examine the dynamics of chromatin reorganization following radiotherapy, we performed a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma (DIPG) and other pediatric high-grade gliomas (pHGG) following IR exposure. We interrogated IR-induced gene expression in the presence or absence of PTEFb blockade, including both mechanistic and functional consequences of concurrent inhibition or genetic depletion. We utilized culture models with live cell imaging to assess the therapeutic synergy of PTEFb inhibition with IR, as well as the therapeutic index of this intervention relative to normal controls. Finally, we employed orthotopic models of pHGG treated with conformal radiotherapy and CNS-penetrant PTEFb inhibitors in order to assess tolerability and anti-tumor effect in vivo. RESULTS: Rapid genome-wide redistribution of active chromatin features and PTEFb facilitates Pol II pause-release to drive nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of PTEFb imparts a transcription elongation defect, abrogating canonical adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. CONCLUSION: These studies reveal a central role for PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies.
Flow cytometry can reliably capture gut microbial composition in healthy adults as well as dysbiosis dynamics in patients with aggressive B-cell non-Hodgkin lymphoma
Authors: Maren Schmiester, René Maier, René Riedel, Pawel Durek, Marco Frentsch, Stefan Kolling, Mir-Farzin Mashreghi, Robert Jenq, Liangliang Zhang, Christine B. Peterson, Lars Bullinger, Hyun-Dong Chang, Il-Kang Na
Journal: Gut Microbes (2022)

Modulation of commensal gut microbiota is increasingly recognized as a promising strategy to reduce mortality in patients with malignant diseases, but monitoring for dysbiosis is generally not routine clinical practice due to equipment, expertise and funding required for sequencing analysis. A low-threshold alternative is microbial diversity profiling by single-cell flow cytometry (FCM), which we compared to 16S rRNA sequencing in human fecal samples and employed to characterize longitudinal changes in the microbiome composition of patients with aggressive B-cell non-Hodgkin lymphoma undergoing chemoimmunotherapy. Diversity measures obtained from both methods were correlated and captured identical trends in microbial community structures, finding no difference in patients' pretreatment alpha or beta diversity compared to healthy controls and a significant and progressive loss of alpha diversity during chemoimmunotherapy. Our results highlight the potential of FCM-based microbiome profiling as a reliable and accessible diagnostic tool that can provide novel insights into cancer therapy-associated dysbiosis dynamics.
Impact of sex on outcomes in patients with hairy cell leukemia (HCL): An HCL Patient Data Registry (PDR) analysis.
Authors: Narendranath Epperla, Qiuhong Zhao, Mirela Anghelina, Jasmine Neal, James Stewart Blachly, Kerry Anne Rogers, Gerard Lozanski, Christopher Oakes, Seema Bhat, Versha Banerji, Clive Zent, Michael R. Grever, Leslie Ann Andritsos
Journal: Journal of Clinical Oncology (2022)

7577 Background: HCL is a rare indolent leukemia that is more common in men, with a 4:1 male predominance. To date, no studies have characterized the potential difference in outcomes of HCL between male and female patients. Hence, we sought to evaluate the outcomes of female HCL patients using the HCL-PDR. Methods: The HCL Foundation sponsored the development of HCL-PDR to characterize the clinical features and outcomes of this rare leukemia. HCL-PDR is an international multicenter PDR that includes patient, disease and treatment information abstracted from medical records. Adult patients enrolled in the HCL-PDR were included in the study. Female patients with HCL were the study population, with males as the comparator. The primary endpoint was the time to next treatment (TTNT) in females compared to males. Secondary endpoints included response rates (RR) and predictors of TTNT. Responses were categorized as: complete response (CR) including CR/CRu (CR unconfirmed)/HR (hematologic response), and partial response (PR), which included PR/PRu (PR unconfirmed)/pHR (partial HR). CRu was defined as no disease in bone marrow (BM) without available blood counts and HR as blood counts meeting criteria for HR, but no available BM. Cox proportional hazard models were used to estimate the hazard ratios for TTNT risk. Results: 357 patients were included: 265 males and 92 females. Table shows baseline characteristics stratified by sex. Among the patients who had disease status assessed after first treatment (n=224, males 169 and females 55), there was no significant difference in RR. However, females had significantly longer median TTNT (17.6 years) relative to males (8 years, HR 0.54, 95% CI 0.32-0.91, p=0.02) that remained significant after adjusting for other variables (RR and BRAF mutation) in multivariable analysis (HR 0.32, 95% CI 0.11-0.97, p=0.04). Factors predictive of longer TTNT include female sex and CR (HR.0.26, 95% CI 0.11-0.57, p=0.001). Conclusions: This is the first study to date reporting the clinical characteristics and outcomes in female HCL patients. The significantly longer TTNT in females compared to males may be related to factors such as underlying molecular features or hormonal influences. This finding needs to be explored further. [Table: see text]
Telephone medical consultation during the COVID-19 pandemic in Mexico.
Authors: Eduardo Rey Torres-Cisneros, Carla Renata Bruni-Guerrero, Juan Manuel Martínez-Valenciano, Rubi Janday Najera, Alan Ledif Reyes Mondragon, Yuridia Evangelina Rodríguez-Rodríguez, Abraham Guerra Cepeda, Adriana González-Gutiérrez, Rolando Jacob Martinez-Granados, Catalina Rodríguez-Moreno, David Hernández-Barajas, Oscar Vidal-Gutiérrez, Carlos Eduardo Salazar-Mejía
Journal: Journal of Clinical Oncology (2022)

e18564 Background: Telephone consultation has emerged as an alternative method for outpatient medical follow-up during the COVID-19 pandemic, reinforcing the necessary distancing measures. However, there are multiple factors that the medical team must contend with, which could limit the monitoring of patients. Methods: We retrospectively analyzed the remote medical consultation database of a university-based oncology referral center in northeast Mexico. The telephone calls were made from the medical center by specialized health personnel. The data obtained correspond to the monitoring conducted over six months. Results: We included 1,140 patients in the analysis, of which 79% were women and 21% were men; the median age was 55 years. All individuals had a pathology-confirmed diagnosis of cancer. The main oncological diagnoses were breast, cervix, and prostate cancer which corresponded to 46, 13, and 7% of the cases, respectively. Ninety-four percent of cases corresponded to cancer surveillance, while the remaining 6% were receiving active oncological treatment, administered orally. Ninety-three percent of the patients were from the city of Monterrey and its metropolitan area, 6% came from the rest of the municipalities of the state of Nuevo Leon, and 1% were from other states of the Mexican Republic. Ninety-eight percent of the patients had a public health insurance as a method of coverage for health services, while 2% received care through private health insurance. At remote follow-up, only 53% of the patients responded to the telephone calls, none of them reported a diagnosis or any symptom of SARS-CoV-2 infection. Among the 536 patients who had a telephone communication failure, 68% did not respond to the call after 4 attempts, while in 32% of these cases the number provided by the patient was incorrect or non-existent. Conclusions: The high rates of failure to establish telephone communication documented in our population of patients with cancer is a worrying phenomenon. As the COVID-19 pandemic progresses worldwide, we must seek to establish measures to optimize logistics for more effective remote communication, to achieve the best possible outcomes.
Cancer Therapy Approval Timings, Review Speed, and Publication of Pivotal Registration Trials in the US and Europe, 2010-2019
Authors: Mark P. Lythgoe, Aakash Desai, Bishal Gyawali, Philip Savage, Jonathan Krell, Jeremy L. Warner, Ali Raza Khaki
Journal: JAMA Network Open (2022)

<h3>Importance</h3> Ensuring patients have access to safe and efficacious medicines in a timely manner is an essential goal for regulatory agencies, one which has particular importance in oncology because of the substantial unmet need for new therapies. The 2 largest regulatory agencies, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), have pivotal global roles, and their recommendations and approvals are frequently followed by other national regulators. <h3>Objective</h3> To compare market authorization dates for new oncology therapies approved in the US and Europe over the past decade and to examine and contrast the regulatory activities of the FDA and EMA in the approval of new cancer medicines. <h3>Design, Setting, and Participants</h3> This cross-sectional study reviewed the FDA and EMA regulatory databases to identify new oncology therapies approved in both the US and Europe from 2010 to 2019, and characterization of the timings of regulatory activities. Statistical analysis was performed from January to April 2022. <h3>Main Outcomes and Measures</h3> Regulatory approval date, review time, submission of market authorization application, accelerated approval or conditional marketing authorization status and proportion of approvals prior to peer-reviewed publication of pivotal trial results. <h3>Results</h3> In total, 89 new concomitant oncology therapies were approved in the US and Europe from 2010 to 2019. The FDA approved 85 oncology therapies (95%) before European authorization and 4 therapies (5%) after. The median (IQR) delay in market authorization for new oncology therapies in Europe was 241 (150-370) days compared with the US. The median (IQR) review time was 200 (155-277) days for the FDA and 426 (358-480) days for the EMA. Sixty-four new licensing applications (72%) were submitted to the FDA first, compared with 21 (23%) to the EMA. Thirty-five oncology therapies (39%) were approved by the FDA prior to pivotal study publication, whereas only 8 (9%) by the EMA. <h3>Conclusion and Relevance</h3> In this cross-sectional study, new oncology therapies were approved earlier in the US than Europe. The FDA received licensing applications sooner and had shorter review times. However, more therapies were approved prior to licensing study publication, leaving uncertainty for practitioners regarding clinical utility and safety of newly approved therapies.
Treatment exposure-based risk-stratification for care of survivors of childhood cancer: A report from the Childhood Cancer Survivor Study.
Authors: Michaela Ann Dinan, Kayla Stratton, Wendy M. Leisenring, Yutaka Yasui, Eric Jessen Chow, Chaya S. Moskowitz, Jennifer M Yeh, David H Noyd, Gregory T. Armstrong, Kevin C. Oeffinger
Journal: Journal of Clinical Oncology (2022)

10056 Background: Treatment exposure-based risk-stratification oflong-term cancer survivors is needed to allocate tailored health care in survivorship clinics. Investigators from the United Kingdom (UK) developed a treatment exposure-based algorithm that stratifies survivors into low, medium, and high risk groups. Because this algorithm has not been validated, we sought to use the large, diverse population of the Childhood Cancer Survivor Study (CCSS) to validate risk for poor outcomes. Methods: Five-year survivors of childhood cancer (diagnosed between 1970-1999 at &lt; 21 years of age) were categorized into low, medium, and high risk groups based on treatment exposures and diagnoses (Table). Primary endpoints included cumulative health-related (i.e., non-recurrence, non-external) late mortality and cumulative incidence of grade 3-5 chronic conditions (CTCAEv4.03) conditional on reaching age 20 without the outcome. Siblings were a comparison group for chronic conditions. Cox proportional hazards models among survivors estimated hazard ratios (HRs) and 95% confidence intervals (CI) adjusted for sex and race. Results: A total of 21,504 survivors were analyzed with a median follow-up of 22 years. Application of the risk stratification algorithm resulted in 3,152 low risk, 6,443 medium risk, and 11,909 high risk survivors. Among those who survived to age 20 without any grade 3-5 conditions, the risk of developing one by age 35 was 12.2% (95% CI 1.0-14.7%), 14.2% (12.8-15.7%) and 25.4% (24.2-26.6%) for low, medium, and high-risk patients, respectively, and 6.9% (6.1-7.9%) for siblings. HRs of grade 3-5 conditions for medium (HR 1.8, 95% CI 1.6-2.1) and high (HR 3.9, 95% CI 3.5-4.4) risk relative to low risk survivors, respectively, were elevated. Cumulative health-related mortality was similarly associated with risk categories; conditional on being alive at age 20, survivors within low, medium, and high risk groups had cumulative incidences of 2.3% (95% CI 1.7-3.1%), 3.3% (2.8-3.9%) and 6.1% (5.6-6.6%), respectively, by age 35. Conclusions: Risk categorizations based on treatment exposures were effective at providing generalized risk stratification within the CCSS with respect to risk of grade 3-5 conditions and health related mortality, particularly for identifying high risk survivors. These risk groups may be useful to physicians in determining follow-up intervals and guiding management and long-term surveillance of these survivors. [Table: see text]
Characteristics of Adults Aged ≥18 Years Evaluated for Substance Use and Treatment Planning — United States, 2019
Authors: Akadia Kacha-Ochana, Christopher M. Jones, Jody L. Green, Christopher Dunphy, Taryn Dailey Govoni, Rebekkah S. Robbins, Gery P. Guy
Journal: MMWR Morbidity and Mortality Weekly Report (2022)

In 2019, 65.8 million U.S. adults reported past-month binge drinking and 35.8 million reported illicit drug use or prescription pain reliever misuse during the past month; 20.4 million met diagnostic criteria for a substance use disorder during the past year (1). Approximately 81,000 persons died of a drug overdose* during May 2019-May 2020; excessive alcohol use contributes to an estimated 95,000 deaths per year (2). Persons with a substance use disorder are at elevated risk for overdose and associated harms (3). To examine the prevalence of past 30-day substance use patterns and the severity of problems experienced across seven biopsychosocial domains (alcohol, drug, employment, family, legal, medical, and psychiatric), CDC used 2019 data from the National Addictions Vigilance Intervention and Prevention Program (NAVIPPRO) Addiction Severity Index-Multimedia Version (ASI-MV) tool (4); these data are collected from adults aged ≥18 years who seek substance use treatment in the United States. Alcohol was the most commonly reported substance used during the past 30 days (35.8%), followed by cannabis (24.9%), prescription opioids (misuse) (18.5%), illicit stimulants (14.0%), heroin (10.2%), prescription sedatives or tranquilizers (misuse) (8.5%), cocaine (7.4%), illicit fentanyl (4.9%), and prescription stimulants (misuse) (1.8%).† Polysubstance use (use of two or more substances) during the past 30 days was reported by 32.6% of respondents. Among the biopsychosocial domains measured, 45.4% of assessments reported more severe problems with drugs; others reported psychiatric (35.2%), legal (28.8%), medical (27.4%), employment (25.0%), alcohol (24.2%), and family problems (22.8%). These findings highlight the complex nature of substance use in the United States, the interplay between substance use and mental illness, and the complex challenges that persons with substance use disorder face when seeking treatment. Actions to enhance comprehensive substance use programs that incorporate polysubstance use and co-occurring mental health problems into strategies for prevention, treatment, and response are needed, as is expanded linkage to services. CDC provides data and resources to equip and inform states, territories, and local jurisdictions to help improve opioid prescribing practices, improve linkage to care for the treatment of opioid use disorder, and prevent and reverse overdoses.§.
pH sensing controls tissue inflammation by modulating cellular metabolism and endo-lysosomal function of immune cells
Authors: Xiangjun Chen, Alok Jaiswal, Zachary Costliow, Paula Herbst, Elizabeth A. Creasey, Noriko Oshiro-Rapley, Mark J. Daly, Kimberly L. Carey, Daniel B. Graham, Ramnik J. Xavier
Journal: Nature Immunology (2022)
OTHR-26. A pilot study of clinical minimal residual disease detection in pediatric embryonal brain tumors
Authors: Bonnie Cole, Christina Lockwood, Vera Paulson, Amy Lee, Jason Hauptman, Hannah Goldstein, Nicholas Vitanza, Erin Crotty, Sarah Leary
Journal: Neuro-Oncology (2022)

Abstract Cell-free DNA (cfDNA) presents an opportunity for measurement of minimal residual disease (MRD) in pediatric central nervous system (CNS) tumors. In this pilot study, we sought to evaluate the clinical use of low-pass whole genome sequencing (LP-WGS) of cfDNA in cerebrospinal fluid (CSF) of patients with embryonal neoplasms. 31 CSF samples were collected from 16 patients with molecularly characterized medulloblastoma (12), embryonal tumor with multilayer rosettes (2), and CNS embryonal tumors, NEC (2). Samples were collected at various treatment time points. Processing included centrifugation and freezing prior to cfDNA extraction, repair, adapter ligation, amplification, purification, and sequencing on an internally-developed and clinically-validated LP-WGS assay utilizing custom-developed bioinformatics and molecular pathologist review. 29 of 31 samples (94%) had adequate cfDNA in CSF for LP-WGS analysis. Copy number variants (CNVs) compatible with tumor were detected in 23 of 29 (79%) samples, including isodicentric chromosome 17, monosomy 6, MYCN amplification, and regional amplification of chromosome 19. In all cases with detectable cfDNA alterations in CSF, CNV were compatible with the molecular findings in tumor tissue. Two CSF samples had additional chromosomal alterations detected at the time of tumor progression that were not identified in the original tumors. All 9 lumbar puncture samples (100%) collected at initial staging had CSF cfDNA alterations indicative of MRD while corresponding cytologic evaluations of the same samples were positive in only 1 of 9 (11%). No MRD was detected in the single sample evaluated at the end of therapy time point. These findings suggest that LP-WGS of cfDNA in CSF represents a sensitive and clinically useful test for detection of MRD in patients with embryonal tumors of the CNS independent from CSF cytology. Future prospective studies are warranted to determine whether LP-WGS analysis of cfDNA in CSF can predict tumor recurrence and early treatment resistance in our patients.
Cystatin SN is a potent upstream initiator of epithelial-derived type 2 inflammation in chronic rhinosinusitis
Authors: Angela L. Nocera, Sarina K. Mueller, Alan D. Workman, Dawei Wu, Kristen McDonnell, Peter M. Sadow, Mansoor M. Amiji, Benjamin S. Bleier
Journal: Journal of Allergy and Clinical Immunology (2022)
ETMR-14. The single-cell landscape of pineoblastoma identifies developmental origins and exposes novel therapeutic vulnerabilities.
Authors: Brian Gudenas, Bernhard Englinger, Anthony P Y Liu, Sheikh Tanveer Ahmad, David Meredith, Elke Pfaff, Leena Paul, Jennifer Hadley, Melissa Batts, Paul Klimo, Frederick A Boop, Amar Gajjar, Giles Robinson, Brent Orr, Hong Lin, Sanda Alexandrescu, David T W Jones, Mariella G Filbin, Paul A Northcott
Journal: Neuro-Oncology (2022)

Abstract Pineoblastoma (PB) is a rare and aggressive childhood brain tumor with highly variable age and treatment-associated outcomes. Our recent bulk tumor analyses of DNA methylation and mutational landscapes uncovered four discrete PB molecular subgroups (PB-miRNA1, PB-miRNA2, PB-MYC/FOXR2, and PB-RB), providing a major advance in our understanding of biological and clinical heterogeneity. However, developmental origins of PB subgroup heterogeneity and mechanisms governing how specific genetic alterations promote malignancy remain unknown. To resolve the cellular origins of PB, we assembled a large single-nucleus RNA-sequencing cohort (n=32) of primary PB tumors, including representatives from each subgroup. Transcriptomic analysis identified subgroup-specific gene expression programs driving intra-tumoral heterogeneity. In addition, we discovered substantial differences in the expression of miRNA biogenesis genes between the PB-miRNA1 and PB-miRNA2 subgroups, providing mechanistic support for their distinct subgroup identities despite overlapping driver events. The MYC/FOXR2 subgroup was characterized by over-expression of the FOXR2 proto-oncogene in bulk RNA-seq, which we validated in single-nuclei and identified co-expressed downstream target genes. To map PB subgroups to their putative developmental beginnings, we created a single-cell transcriptional atlas of the murine pineal gland across 11 developmental stages (E11-P21). Trajectory inference within the developing pineal gland revealed a differentiation continuum of early, mid, and mature alpha-/beta pinealocytes. Cross-species correlation and deconvolution identified significant associations between multiple PB subgroups and specific differentiation states of the pinealocyte lineage, suggestive of developmental origins. Characterization of pinealocyte development informed generation of biologically faithful disease models, including a novel genetically engineered mouse model of the PB-RB subgroup. PB-Rb1 mouse tumors were histologically and molecularly validated for their fidelity to human tumor counterparts, exhibiting up-regulation of key pinealocyte lineage markers that are diagnostic in patients. Finally, high-throughput drug screening identified several promising pharmacological candidates that may attenuate consequences of Rb1 deficiency in affected children.